The structure and physical properties of human non-pancreatic secretory phospholipase A.sub.2 (hereinafter called, "sPLA.sub.2 ") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A.sub.2 Present in Rheumatoid Arthritic Synovial Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and "Structure and Properties of a Human Non-pancreatic Phospholipase A.sub.2 " by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA.sub.2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA.sub.2 mediated release of fatty acids (e.g., arachidonic acid) and are highly bioavailable in mammals, especially humans. Such compounds are of value in general treatment of conditions induced and/or maintained by overproduction of sPLA.sub.2 ; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.
Therapeutic agents that may be given orally are, in general, greatly preferred and have enhanced commercial potential because of their inherent ease of use.
Glycolamide esters as prodrugs are described in the chemical literature, for example; (1) "Evaluation of Glycolamide Esters and Various Other Esters of Aspirin as True Aspirin Prodrugs" by Niels Mork Nielsen and Hans Bundgaard, J. Med. Chem. 1989, Vol. 32, pp. 727-734; and (2) "Glycolamide Esters as Biolabile Prodrugs of Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and Physicochemical Properties" by Niels Mork Nielsen and Hans Bundgaard, Journal of Pharmaceutical Sciences, Vol. 77, No. 4, April 1988.
U.S. Pat. No. 5,654,326 describes certain indole type sPLA.sub.2 inhibitors. In particular, this patent exemplifies the methyl ester of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1'-biphenyl)-3-ylmethyl)-2-methyl-1H-in dol-4-yl)oxy)acetic acid.
It is desirable to develop more highly available sPLA.sub.2 inhibitors, particularly those suitable for oral administration.